肝细胞癌（HCC）起源于完全分化的肝细胞，但将肝细胞转化为HCC起源细胞的决定性事件仍不清楚。肝癌干细胞（LCSCs）会引发HCC，但并非正宗的起源细胞。在乙基二硝基胺挑战下的小鼠中，发现在肉眼正常的肝脏中存在POU2F2和IL-31的表达。POU2F2和IL-31之间相互诱导形成的自身调控回路，驱动肝细胞进展为LCSCs并获得干细胞特性，同时促使其在体内生长和恶性进展。自身调控回路的发展是将肝细胞转化为起源细胞的决定性事件，因为在进展为LCSCs之前表达该回路的肝细胞已经获得了肿瘤形成潜能。然而，起源细胞仍需要获得干细胞特性来启动肝癌发生。该回路在人类肝硬化组织中也存在，部分阐明了如何从癌前病变进展为HCC。© 2021 The Authors. Advanced Science published by Wiley‐VCH GmbH.

Hepatocellular carcinoma (HCC) originates from fully differentiated hepatocytes, but the decisive events for converting hepatocytes to the cells of origin for HCC are still unclear. Liver cancer stem cells (LCSCs) cause HCC but are not bona fide cells of origin. Here, the expressions of POU2F2 and IL-31 are identified in macroscopically normal livers of diethylnitrosamine-challenged mice. An autoregulatory circuit formed by mutual induction between POU2F2 and IL-31 drives hepatocytes to progress to LCSCs by acquiring stemness, as well as stimulates them to in vivo grow and malignantly progress. The development of the autoregulatory circuit is a decisive event for converting hepatocytes into the cells of origin, since hepatocytes expressing the circuit have acquired tumorigenic potential before progressing to LCSCs. Nonetheless, acquiring stemness is still required for the cells of origin to initiate hepatocarcinogenesis. The circuit also occurs in human cirrhotic tissues, partially elucidating how premalignant lesions progress to HCC.© 2021 The Authors. Advanced Science published by Wiley‐VCH GmbH.